Penn Researchers Determine Structure
of Binding Site of Colon-Cancer Drug and Its Protein
TargetFinding Will Steer Future Treatment Design

(Philadelphia, PA) - Researchers at the University
of Pennsylvania School of Medicine have determined
the precise molecular details of how Erbitux, a recently
approved colorectal cancer drug, binds to its target
on cancer cells. Knowing this chemical configuration
will lead to better drug design for this family of cancer
medications.

Colorectal cancer is one of the most frequently diagnosed
cancers in men and women, as well as the second-leading
cause of cancer-related death, according to the Centers
for Disease Control and Prevention. Erbitux works by
binding to a protein on the surface of cancer cells,
thereby halting excessive cell growth that leads to
tumors. Kate Ferguson, PhD, Assistant
Professor of Physiology, and colleagues, describe their
findings in the April cover article of Cancer Cell.

“By having determined the structure of Erbitux
bound to its cellular target receptor, we get new insight
into how the drug blocks the receptor’s cell growth-promoting
activities, and can use this to guide future drug design,”
says Ferguson.

As
is characteristic of many epithelial cancers - such
as cancers of the head and neck, breast, ovary, lung,
and pancreas - the surface of cancer cells possess abnormally
high levels of epidermal growth factor receptor (EGFR),
the protein that interacts with Erbitux. (Click on thumbnail
to view full-size image). These receptors are made up
of three parts: one outside the cell; another passing
through the cell membrane; and the third inside the
cell. In a cancer cell, an extracellular hormone binds
to the outer piece of EGFR, and causes the inside part
to kick off a series of reactions that signal the cancerous
cell to replicate and divide.

Ferguson and colleagues determined that Erbitux works
to halt cell proliferation by blocking EGFR’s
molecular doorway, disallowing hormones to bind and
signal tumor growth. X-ray crystallography provided
a snapshot of the interaction between Erbitux and the
extracellular component of the cancer cell’s receptors.

The resulting structural information deciphered by Ferguson
and colleagues emphasizes the importance of drug research
targeting active protein receptors on cancer cells and
tumors. As is the case in Erbitux, “the protein
EGFR needs to not only be present on tumors but it needs
to be there and be active,” says Ferguson.

“Understanding the structure could help us design
alternatives to Erbitux that would be easier to deliver
in small-molecule medications to be taken as a pill,”
as opposed to the current intravenous administration
of the drug, Ferguson adds. The researchers’ hope
is that with these new insights into Erbitux’s
action and structure, treatments for colorectal cancer
and other epithelial cancers will be expanded, thereby
contributing to the creation of future generations of
improved cancer drugs.

The study was funded by the National Institutes of Health,
the Burroughs Wellcome Fund, and ImClone Systems Inc.
Study co-authors Paul Kussie and Jed. J.W. Wiltzius
are employees of ImClone, the manufacturer of Erbitux.
Shiqing Li and Karl R. Schmitz from Penn, and Philip
D. Jeffrey (formerly from the Memorial Sloan-Kettering
Cancer Center and now Princeton University) are also
co-authors. The authors report no conflicts of interest
related to this research.

PENN Medicine is a $2.7 billion
enterprise dedicated to the related missions of medical
education, biomedical research, and high-quality patient
care. PENN Medicine consists of the University of Pennsylvania
School of Medicine (founded in 1765 as the nation’s
first medical school) and the University of Pennsylvania
Health System.

Penn’s School of Medicine is ranked #3 in the
nation for receipt of NIH research funds; and ranked
#4 in the nation in U.S. News & World Report’s
most recent ranking of top research-oriented medical
schools. Supporting 1,400 fulltime faculty and 700 students,
the School of Medicine is recognized worldwide for its
superior education and training of the next generation
of physician-scientists and leaders of academic medicine.

Penn Health System is comprised of: its flagship hospital,
the Hospital of the University of Pennsylvania, consistently
rated one of the nation’s “Honor Roll”
hospitals by U.S. News & World Report; Pennsylvania
Hospital, the nation's first hospital; Presbyterian
Medical Center; a faculty practice plan; a primary-care
provider network; two multispecialty satellite facilities;
and home health care and hospice.